鸟苷酸环化酶 (GC)-A 和其他膜 GC 受体的磷酸化依赖性调控

IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Lincoln R Potter
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引用次数: 0

摘要

受体鸟苷酸环化酶(GCs)是一种跨膜的多域酶,可在钠尿肽或其他配体的作用下合成 cGMP。从海胆到人类,它们在进化过程中保持一致,并调节着不同的生理机能。大多数家族成员在其激酶同源结构域起始处的四到七个保守丝氨酸或苏氨酸上被磷酸化。本综述介绍了证明这些酶的激活和失活分别需要磷酸化和去磷酸化的研究。本文讨论了 GC-A、GC-B、GC-E 和海胆受体中的磷酸化位点,以及分别模拟 GC-A 和 GC-B 的去磷酸化、非活性或磷酸化、活性形式的突变受体。描述的盐桥模型解释了酶激活需要磷酸化的原因。还讨论了 GC 受体的潜在激酶、磷酸酶和 ATP 调节。重要的是,描述了受体磷酸化位点被谷氨酸取代的基因敲入小鼠。在 GC-A 或 GC-B 不能去磷酸化的小鼠中,相反的信号通路不能抑制 cGMP 合成,这证明了体内受体去磷酸化的必要性。心脏肥大、卵母细胞减数分裂、长骨生长/软骨增生和骨密度受 GC 磷酸化调节,但未来可能还会发现其他过程。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Phosphorylation-Dependent Regulation of Guanylyl Cyclase (GC)-A and Other Membrane GC Receptors.

Receptor guanylyl cyclases (GCs) are single membrane spanning, multidomain enzymes, that synthesize cGMP in response to natriuretic peptides or other ligands. They are evolutionarily conserved from sea urchins to humans and regulate diverse physiologies. Most family members are phosphorylated on 4 to 7 conserved serines or threonines at the beginning of their kinase homology domains. This review describes studies that demonstrate that phosphorylation and dephosphorylation are required for activation and inactivation of these enzymes, respectively. Phosphorylation sites in GC-A, GC-B, GC-E, and sea urchin receptors are discussed, as are mutant receptors that mimic the dephosphorylated inactive or phosphorylated active forms of GC-A and GC-B, respectively. A salt bridge model is described that explains why phosphorylation is required for enzyme activation. Potential kinases, phosphatases, and ATP regulation of GC receptors are also discussed. Critically, knock-in mice with glutamate substitutions for receptor phosphorylation sites are described. The inability of opposing signaling pathways to inhibit cGMP synthesis in mice where GC-A or GC-B cannot be dephosphorylated demonstrates the necessity of receptor dephosphorylation in vivo. Cardiac hypertrophy, oocyte meiosis, long-bone growth/achondroplasia, and bone density are regulated by GC phosphorylation, but additional processes are likely to be identified in the future.

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来源期刊
Endocrine reviews
Endocrine reviews 医学-内分泌学与代谢
CiteScore
42.00
自引率
1.00%
发文量
29
期刊介绍: Endocrine Reviews, published bimonthly, features concise timely reviews updating key mechanistic and clinical concepts, alongside comprehensive, authoritative articles covering both experimental and clinical endocrinology themes. The journal considers topics informing clinical practice based on emerging and established evidence from clinical research. It also reviews advances in endocrine science stemming from studies in cell biology, immunology, pharmacology, genetics, molecular biology, neuroscience, reproductive medicine, and pediatric endocrinology.
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